본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

ACS chemical neuroscience v.8 no.1, 2017년, pp.165 - 177   SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Wager, Travis T. (Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, ) ; Chappie, Thomas (Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, ) ; Horton, David (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, ) ; Chandrasekaran, Ramalakshmi Y. (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, ) ; Samas, Brian (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, ) ; Dunn-Sims, Elizabeth R. (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, ) ; Hsu, Cathleen (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, ) ; Nawreen, Nawshaba (Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 0 ) ; Vanase-Frawley, Michelle A. ; O'Connor, Rebecca E. ; Schmidt, Christopher J. ; Dlugolenski, Keith ; Stratman, Nancy C. ; Majchrzak, Mark J. ; Kormos, Bethany L. ; Nguyen, David P. ; Sawant-Basak, Aarti ; Mead, Andy N. ;
  • 초록  

    Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1 . Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 ( 3 ). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K i = 3.1 nM), good subtype selectivity over D2R (D2 K i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction. Graphic Abstract ACS Electronic Supporting Info


  • 주제어

    Substance use dependence .   drug addiction .   CNS MPO .   dopamine D3 antagonist .   dopamine D2 antagonist .   opioid .   cessation .   drug-seeking behavior .   reinstatement .   extrapyramidal symptoms .   locomotor.  

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • 원문이 없습니다.
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기